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Structure of the mycobacterial ESX-5 Type VII Secretion System hexameric pore complex

View ORCID ProfileKathrine S. H. Beckham, View ORCID ProfileChristina Ritter, View ORCID ProfileGrzegorz Chojnowski, View ORCID ProfileEdukondalu Mullapudi, Mandy Rettel, Mikhail M. Savitski, Simon A. Mortensen, View ORCID ProfileJan Kosinski, View ORCID ProfileMatthias Wilmanns
doi: https://doi.org/10.1101/2020.11.17.387225
Kathrine S. H. Beckham
1European Molecular Biology Laboratory, Hamburg Unit, Notkestrasse 85, 22607 Hamburg, Germany
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Christina Ritter
1European Molecular Biology Laboratory, Hamburg Unit, Notkestrasse 85, 22607 Hamburg, Germany
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  • ORCID record for Christina Ritter
Grzegorz Chojnowski
1European Molecular Biology Laboratory, Hamburg Unit, Notkestrasse 85, 22607 Hamburg, Germany
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Edukondalu Mullapudi
1European Molecular Biology Laboratory, Hamburg Unit, Notkestrasse 85, 22607 Hamburg, Germany
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Mandy Rettel
2European Molecular Biology Laboratory, Heidelberg, Germany
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Mikhail M. Savitski
2European Molecular Biology Laboratory, Heidelberg, Germany
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Simon A. Mortensen
1European Molecular Biology Laboratory, Hamburg Unit, Notkestrasse 85, 22607 Hamburg, Germany
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Jan Kosinski
1European Molecular Biology Laboratory, Hamburg Unit, Notkestrasse 85, 22607 Hamburg, Germany
3Centre for Structural Systems Biology (CSSB), Hamburg, Germany
4Structural and Computational Biology Unit, European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117, Heidelberg, Germany
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  • For correspondence: jan.kosinski@embl.de matthias.wilmanns@embl-hamburg.de
Matthias Wilmanns
1European Molecular Biology Laboratory, Hamburg Unit, Notkestrasse 85, 22607 Hamburg, Germany
5University Hamburg Clinical Centre Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany
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  • For correspondence: jan.kosinski@embl.de matthias.wilmanns@embl-hamburg.de
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Abstract

To establish an infection, pathogenic mycobacteria use the Type VII secretion or ESX system to secrete virulence proteins across their cell envelope. The five ESX systems (ESX-1 to ESX-5) have evolved diverse functions in the cell, with the ESX-5 found almost exclusively in pathogens. Here we present a high-resolution cryo-electron microscopy structure of the hexameric ESX-5 Type VII secretion system. This 2.1 MDa membrane protein complex is built by a total of 30 subunits from six protomeric units, which are composed of the core components EccB5, EccC5, two copies of EccD5, and EccE5. The hexameric assembly of the overall ESX-5 complex is defined by specific inter-protomer interactions mediated by EccB5 and EccC5. The central transmembrane pore is formed by six pairs of EccC5 transmembrane helices that adopt a closed conformation in the absence of substrate in our structure. On the periplasmic face of the ESX-5 complex, we observe an extended arrangement of the six EccB5 subunits around a central cleft. Our structural findings provide molecular details of ESX-5 assembly and observations of the central secretion pore, which reveal insights into possible gating mechanisms used to regulate the transport of substrates.

Competing Interest Statement

The authors have declared no competing interest.

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Posted November 17, 2020.
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Structure of the mycobacterial ESX-5 Type VII Secretion System hexameric pore complex
Kathrine S. H. Beckham, Christina Ritter, Grzegorz Chojnowski, Edukondalu Mullapudi, Mandy Rettel, Mikhail M. Savitski, Simon A. Mortensen, Jan Kosinski, Matthias Wilmanns
bioRxiv 2020.11.17.387225; doi: https://doi.org/10.1101/2020.11.17.387225
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Structure of the mycobacterial ESX-5 Type VII Secretion System hexameric pore complex
Kathrine S. H. Beckham, Christina Ritter, Grzegorz Chojnowski, Edukondalu Mullapudi, Mandy Rettel, Mikhail M. Savitski, Simon A. Mortensen, Jan Kosinski, Matthias Wilmanns
bioRxiv 2020.11.17.387225; doi: https://doi.org/10.1101/2020.11.17.387225

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